DNA Mismatch Repair Preferentially Protects Genes from Mutation
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB22916 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2163280.fastq.gz | Fastqsanger.gz | |||
| ERR2163290.fastq.gz | Fastqsanger.gz | |||
| ERR2163300.fastq.gz | Fastqsanger.gz | |||
| ERR2163310.fastq.gz | Fastqsanger.gz | |||
| ERR2163320.fastq.gz | Fastqsanger.gz |
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Project description:Mutation is the source of genetic variation and fuels biological evolution. Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism. Here, we determine the genome-wide effects of MMR on mutation. We first identify almost 9000 mutations accumulated over five generations in eight MMR-deficient mutation accumulation (MA) lines of the model plant species, Arabidopsis thaliana We then show that MMR deficiency greatly increases the frequency of both smaller-scale insertions and deletions (indels) and of single-nucleotide variant (SNV) mutations. Most indels involve A or T nucleotides and occur preferentially in homopolymeric (poly A or poly T) genomic stretches. In addition, we find that the likelihood of occurrence of indels in homopolymeric stretches is strongly related to stretch length, and that this relationship causes ultrahigh localized mutation rates in specific homopolymeric stretch regions. For SNVs, we show that MMR deficiency both increases their frequency and changes their molecular mutational spectrum, causing further enhancement of the GC to AT bias characteristic of organisms with normal MMR function. Our final genome-wide analyses show that MMR deficiency disproportionately increases the numbers of SNVs in genes, rather than in nongenic regions of the genome. This latter observation indicates that MMR preferentially protects genes from mutation and has important consequences for understanding the evolution of genomes during both natural selection and human tumor growth.
| S-EPMC5749183 | biostudies-literature
Project description:Histone H3 trimethylation at lysine 36 (H3K36me3) is an important histone mark involved in both transcription elongation and DNA mismatch repair (MMR). It is known that H3K36me3 recruits the mismatch-recognition protein MutSα to replicating chromatin via its physical interaction with MutSα's PWWP domain, but the exact role of H3K36me3 in transcription is undefined. Using ChIP combined with whole-genome DNA sequencing analysis, we demonstrate here that H3K36me3, together with MutSα, is involved in protecting against mutation, preferentially in actively transcribed genomic regions. We found that H3K36me3 and MutSα are much more co-enriched in exons and actively transcribed regions than in introns and nontranscribed regions. The H3K36me3-MutSα co-enrichment correlated with a much lower mutation frequency in exons and actively transcribed regions than in introns and nontranscribed regions. Correspondingly, depleting H3K36me3 or disrupting the H3K36me3-MutSα interaction elevated the spontaneous mutation frequency in actively transcribed genes, but it had little influence on the mutation frequency in nontranscribed or transcriptionally inactive regions. Similarly, H2O2-induced mutations, which mainly cause base oxidations, preferentially occurred in actively transcribed genes in MMR-deficient cells. The data presented here suggest that H3K36me3-mediated MMR preferentially safeguards actively transcribed genes not only during replication by efficiently correcting mispairs in early replicating chromatin but also during transcription by directly or indirectly removing DNA lesions associated with a persistently open chromatin structure.
| S-EPMC5961058 | biostudies-literature
Project description:Only a small proportion of cases suspected to have Lynch Syndrome (LS) can be explained by mutation in the mismatch repair (MMR) genes. This study aimed to identify rare CNVs that may contribute to an increased risk for hereditary colorectal cancer in patients with MMR proficiency.
2015-11-30 | GSE72667 | GEO
Project description:Only a small proportion of cases suspected to have Lynch Syndrome (LS) can be explained by mutation in the mismatch repair (MMR) genes. This study aimed to identify rare CNVs that may contribute to an increased risk for hereditary colorectal cancer in patients with MMR proficiency.
2015-11-30 | GSE72665 | GEO
Project description:The mismatch repair (MMR) family is a highly conserved group of proteins that function in correcting base-base and insertion-deletion mismatches generated during DNA replication. To systematically investigate the mismatch repair pathway, we conducted a proteomic analysis and identified MMR-associated protein complexes using a tandem-affinity purification coupled with mass spectrometry (TAP-MS) method. In total, we identified 262 high-confidence candidate interaction proteins (HCIPs).
2016-02-08 | PXD003014 | Pride
Project description:DNA mismatch repair (MMR) is an evolutionarily conserved process that corrects innate DNA polymerase infidelities during replication to maintain genomic integrity. Defects in a subset of MMR genes are associated with hereditary non-polyposis colon cancer and some other sporadic cancers, highlighting the crucial role for MMR in genome maintenance. In E. coli a helicase implicated in the MMR process is well characterized, and named UvrD, whereas in mammals it has not been identified yet, even though the eukaryotic DNA mismatch pathway is analogous to the bacterial one and uses a similar repair mechanism and key components. Here we identify MCM9 as a helicase playing a vital role in MMR in mammals. MCM9 is the last discovered member of the MCM2-9 family, and has been implicated in replication and homologous recombination processes. By an affinity-purification proteomic approach, we found that MCM9 interacts with the MMR initiation complex. Immortalized cells from MCM9 knockout mice showed clear length alterations in their microsatellites, and a dramatic MMR deficiency compared to wild-type cells. We also found that a helicase-dead form of MCM9 is totally unable to restore the MMR deficiency phenotype. Furthermore, using an siRNA approach in human cells, we demonstrated that MCM9 is regulated by MSH2, a protein responsible for mismatch recognition. Our results clearly reveal that MCM9 functions as a helicase for DNA mismatch repair in mammals, and thus is essential for the maintenance of genome stability. Proteomics analysis: FLAG-HA-tagged human MCM9 plus associated proteins were isolated by tandem affinity purification from nuclear extracts of stably-expressing HeLa S3 cells, then analysed by SDS-PAGE and silver staining. Gel lanes were cut into slices, which were processed and analysed separately. Proteins in each gel slice were digested with trypsin, extracted and analysed by LC-MS/MS on a Thermo Scientific LTQ Velos mass spectrometer, generating a series of MS RAW files. Bioinformatics: Peptide and protein identification from MS data was performed using the Sequest program, with a human IPI sequence database (v.3.60). Trypsin was defined as the protease used, a peptide mass tolerance of 2.5 was specified, and all peptide matches have a Sequest Xcorr score ≥0.5.
2015-08-19 | PXD000212 | Pride
Project description:The DNA mismatch repair (MMR) system promotes genome stability and protects humans from certain types of cancer. Its primary function is the correction of DNA polymerase errors. MutLα is an important eukaryotic MMR factor. We have examined the contributions of MutLα to maintaining genome stability. We show here that loss of MutLα in yeast increases the genome-wide mutation rate by ∼130-fold and generates a genome-wide mutation spectrum that consists of small indels and base substitutions. We also show that loss of yeast MutLα leads to error-prone MMR that produces T > C base substitutions in 5'-ATA-3' sequences. In agreement with this finding, our examination of human whole-genome DNA sequencing data has revealed that loss of MutLα in induced pluripotent stem cells triggers error-prone MMR that leads to the formation of T > C mutations in 5'-NTN-3' sequences. Our further analysis has shown that MutLα-independent MMR plays a role in suppressing base substitutions in N3 homopolymeric runs. In addition, we describe that MutLα preferentially protects noncoding DNA from mutations. Our study defines the contributions of MutLα-dependent and independent mechanisms to genome-wide MMR.
| S-EPMC11231602 | biostudies-literature
Project description:Tumor mutation burden (TMB) is an evolving biomarker for predicting response to immune checkpoint inhibitors (ICI’s). The goal of this study was to evaluate the use of RNA-seq for determining TMB in patients with defective DNA MMR (dMMR) due to MMR mutations or MLH1 promoter hypermethylation (HM) and tumors without dMMR. We included tumors and paired normal tissue from 58 patients for TMB analysis using RNA-seq. Forty-six tumors were MSI-H (29 with a DNA MMR germline mutation and 17 with MLH1 promoter HM) and 12 were MSS. TMB was measured using the expressed somatic nucleotide variants (eTMB). We developed a method that leverages mutational signatures to remove FFPE derived artifact from total eTMB and thereby accurately measure the eTMB. There was a significant difference in the eTMB observed between MSI-H and MSS cases; MSI-H cases had a median of 27.3 mutations/Mb compared to 6.7 mutations/Mb for MSS cases (p=3.5e-9). Among tumors with dMMR the tumors with DNA MMR mutations had a significantly higher eTMB (p=0.037) than tumors with MLH1 promoter HM: a median of 28.1 mutations/Mb vs. a median of 17.5 mutations/Mb. Furthermore, through multivariate analysis we found that MSI status, tissue type (endometrial or colorectal) and patient ages are significantly associated with eTMB. These results demonstrate that RNA-seq analysis can be used to measure eTMB in FFPE tumor specimens. Further studies are needed to determine how eTMB as determined by RNA-seq compares to TMB as determined by DNA-based NGS assays
2020-03-13 | GSE146889 | GEO
Project description:The mismatch repair (MMR) family is a highly conserved group of proteins that function in correcting base-base and insertion-deletion mismatches generated during DNA replication. To systematically investigate the mismatch repair pathway, we conducted a proteomic analysis and identified MMR-associated protein complexes using a tandem-affinity purification coupled with mass spectrometry (TAP-MS) method. In total, we identified 262 high-confidence candidate interaction proteins (HCIPs).
2016-03-13 | MSV000079578 | MassIVE
Project description:The spontaneous mutation rate is a crucial parameter in molecular evolution which is maintained very low. To better characterize how proofreading activity of the DNA polymerase and Mismatch repair (MMR) which are ubiquitous in all kingdoms of life shape a mutational landscape we built B. subtilis 168-derived strains allowing conditional inactivation of either one or both of these two error reparation mechanisms. In practice, we used an IPTG-inducible promoter to control the expression of mutant alleles selected for their ability to displace by competition their functional counterparts. The first allele, denoted here mutL*, has a mutation in the ATP hydrolysis active site of MutL. The second allele, denoted here polC* encodes an exonuclease-deficient variant of PolC. Fluctuation tests and Mutation Accumulation experiments confirmed extremely high mutation rates, upon IPTG-induction, in the strain that combine these two deficient alleles in a synthetic operon (mutL*//polC*). The purpose of this transcritomic study was to better characterize this inducible system. Analysis of the data did not reveal specific transcriptional responses of the bacterium to IPTG addition and extreme mutations rates.
2024-03-25 | GSE239804 | GEO